This invention relates to 5-methyl-5-deaza analogues of methotrexate and N.sup.10 -ethylaminopterin and to the use of such compounds as antineoplastic agents.
Methotrexate (MTX) remains the only classical antifolate in established clinical use, and its use has continued to expand as new methods of administering the drug have been introduced and as other tumor types have been added to the list of those now being treated. MTX usage, however, suffers major limitations due to its toxic side effects and the development of resistance by tumor cells. Some tumors are naturally resistant to MTX while other acquire resistance after a period of response. Three factors known to contribute to drug resistance are (a) loss of the active-transport system by which MTX enters cells, (b) increased levels of dihydrofolate reductase (DHFR), the intracellular target of MTX, and (c) the presence of structurally altered DHFR having lower affinity for MTX. Another explanation of resistance may be offered in the recent description of a structurally altered DHFR from an MTX-resistant mutant cell line with unaltered affinity for MTX, but with greater capacity to reduce dihydrofolate than the DHFR from the parent MTX-sensitive cell line. MTX and aminopterin (AMT) have the following structures: ##STR1##
As part of a program aimed toward the identification of new antifolate agents that exert greater therapeutic effectiveness against a broader spectrum of tumors than agents now available, antifolates are sought having favorably altered transport characteristics but still possessing tight binding affinity for DHFR. In studies aimed toward greater understanding of transport properties, differences have been observed between tumor and normal proliferative tissue in mediated cellular membrane transport of antifolates and in the intracellular .gamma.-polyglutamylation of the agents. These biochemical parameters appear to be critical determinants for selective antitumor activity. In studies that document these differences, positions 5 and 10 on the classical antifolate-type molecular structure have been identified as sites where modification does not reduce binding to DHFR but does influence transport efficacy to favor inward flux into tumor cells and also intracellular .gamma.-polyglutamylation resulting in greater accumulation in tumor cells than in normal cells.
In the discussion which follows, reference will be made to underlined numbers which identify compounds shown by structural formulas in Scheme I. Scheme I is as follows: ##STR2##
In Scheme I, compounds 3, 5, 7, 9, and 11 are disclosed by Elslager et al, "Synthesis of Fused Pyrimidines as Folate Antagonists", presented during the Fourth International Congress of Heterocyclic Chemistry, University of Utah, Salt Lake City, Utah, July 8-13, 1973; published in Lect. Heterocycl. Chem., Vol. II, pps. S-97 to S-132 (1974), see especially pps. S-120 to S-121. Schmidt et al, Monatsch. Chem., Vol. 108, pps. 895 to 900 (1977) teaches the preparation of 2-amino-6-chloro-3,5-dycano-(4-alkyl)-pyridines which includes compound 4 is Scheme I. Compounds 4, 6, 8, 10 and 12 of Scheme I are homologues of compounds disclosed by Elslager et al, supra; and compounds 12, 13, 14, 15, 18, 19, 20, and 21, are homologues of compounds disclosed by U.S. Pat. No. 4,536,575 to Temple et al.